Pediatric-Onset MS: Diagnosis & Management in a Burgeoning Field

Podcast Transcript

Intro: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab and psychiatry.

Glen Stevens, DO, PhD: Relapsing-remitting multiple sclerosis is the majority course for children diagnosed with multiple sclerosis. Although children may experience frequent relapses, studies have shown that recovery in this population is often far more rapid than that of adults. The challenge with pediatric MS lies in the differential diagnosis, but the upshot is powerful. Early intervention after diagnosis can yield positive, long-term effects.

In today's episode of Neuro Pathways, we're discussing differential diagnosis in pediatric multiple sclerosis and the collaborative work of pediatric and adult neuroimmunologists to move the field forward. I am your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's neurological Institute. I am very pleased to have Dr. Aaron Abrams join me for today's conversation. Dr. Abrams is a pediatric neurologist and neuroimmunologist in Cleveland Clinic's Department of Pediatric Neurology and the Mellen Center for Multiple Sclerosis. Aaron, welcome to Neuro Pathways.

Aaron Abrams, MD: Thank you so much, it's really great to be here.

Glen Stevens, DO, PhD: To start things off, the field of pediatric neuroimmunology has really evolved in recent years. It was just in 2018 that the FDA approved the first drug for use in pediatric relapsing-remitting multiple sclerosis. Can you start off our conversation today by talking about how far we've come in identifying demyelinating and neuroimmunologic disease in children? Maybe you could just even start and tell us a little bit about the epidemiology, who's it involved, what kind of numbers, those sorts of things.

Aaron Abrams, MD: Pediatric neurology is a fast moving, rapidly emerging field. We have come a long way in the past 10 or 15 years, but we do have a lot more work to do. That's very much where my passion lies, is both research and clinical exploration of these types of demyelinating diseases, as well as autoimmune encephalitides in the pediatric age group. Regarding your question for specifically disease-modifying therapies in pediatric MS, fingolimod has been approved, and it's really the only one that's been FDA approved, but a big reason for that is really because we are just starting to peel back the onion layers of pediatric MS clinical trials and testing out of these medications in the pediatric MS population. Emerging evidence does suggest that for pediatric MS, the disease-modifying therapies that conventionally are used in adult multiple sclerosis are as effective and also as safe in pediatrics, although the data, again, is not quite as robust, mainly because of the limitation in doing trials in the pediatric population.

Pediatric MS constitutes, we think estimates are around 5% of all multiple sclerosis. It's termed pediatric-onset multiple sclerosis when it occurs before the age of 18. But we do think that both because of diagnostic techniques in terms of advancements and resolution of MRI, as well as increasing awareness amongst pediatric providers and neurologists, we do think that that number is probably going to go up. I think that that's a very important aspect of this, is that with these advances and techniques, we are able, I think, to diagnose a wide spectrum of these diseases earlier and earlier in a person's lifespan.

Glen Stevens, DO, PhD: To that end, and you transitioned me nicely, can you talk to us about some of the tools at your disposal for diagnosing not only pediatric MS, but other pediatric demyelinating disorders or encephalitides or similar disorders in the differential?

Aaron Abrams, MD: Certainly. I think that one of the biggest advances, and one of the most exciting parts of the field, is regarding biomarkers, and specifically autoimmune antibodies within both the blood as well as the cerebral spinal fluid. More and more we're honing the techniques of both identifying new antibodies and markers, but also, importantly, we are making big strides in terms of being able to diagnose diseases with respect to specificity of those biomarkers and confirmatory tests in order to give us the most robust and definitive answers on confirming some of these diseases. Specifically, things like MOG antibody disease or MOG-associated disease is one of the big autoimmune markers that we have come a long way in terms of doing cell-based assays, which has really increased the accuracy with which we're able to detect these types of diseases. That also goes along with things like NMO. All of these really can present in the pediatric age group. Part of my job and what I want to do is to increase that awareness.

Other techniques that we've made big strides with are MRI technology, in terms of both resolution as well as the types of sequencing that we're able to do within MRI protocols in order to better detect and distinguish between demyelinating-type lesions, as opposed to other inflammatory lesions that may be more related to an autoimmune encephalitis, as well as vasculitis-type lesions, using all of these very advanced MRI techniques. Other testing, similar to what we do use as well in the adult MS and adult neuroimmunology field, includes vision testing with visual evoked potentials and OCT testing in order to better detect and give supporting evidence for demyelination as opposed to some of these other types of disorders.

Glen Stevens, DO, PhD: Just for those of the folks that are listening that aren't in the field, I'll just explain that NMO is neuromyelitis optica and NMOSD is neuromyelitis optica spectrum disorder, for what you're discussing with the NMO antibodies and the MOG antibodies for those that aren't in the area. Are there any diagnostic tests that are just done in the pediatric group that aren't done in the adult, or are done in the adult and not the pediatric, or pretty much the same can be done in each group?

Aaron Abrams, MD: In general, I would say that that similar testing is done in each group. However, I think one of the big distinguishing features is regarding neurocognitive testing, and specifically formal neuropsychological evaluation. I think that that tends to be more utilized in the pediatric population because we do feel that with pediatrics, oftentimes children will bounce back and recover very well with respect to their neurological deficits, in terms of motor deficits and sensory problems, being able to walk and weakness and those kinds of things, but what we find is that with pediatrics there still is a significant burden on the cognitive realm and in terms of potentially academic performance. I think one of the things that we tend to focus more on within pediatrics, as opposed to the adult population, is regarding neuropsychological batteries and neuropsychological testing as a potential both, marker of disease involvement, but also in order to monitor therapeutic response moving forward.

Glen Stevens, DO, PhD: You had mentioned as well, I think, OCT, the optical coherence tomography. Is there an age at which children can sit for that, that you find?

Aaron Abrams, MD: Typically, it's difficult to do it below the age of five, and some would say even seven or eight. It's difficult to do the visual testing, which again creates more challenges and really requires a more reliance both on MRI sensitivities, as well as these types of autoimmune antibody testings, as well as, I think, focusing on, similar to the neuropsychological piece, development, especially in young, young children. It is one of the things that is limited, in terms of looking at optic neuritis and things that very often are involved when it comes to multiple sclerosis and many other of these demyelinating type diseases.

Glen Stevens, DO, PhD: Clearly there's a lot of current therapies out for adult-onset MS. We had mentioned the fingolimod was released in 2018. Anything else approved since 2018, or not yet?

Aaron Abrams, MD: None have been FDA approved, but there have been more and more studies being done within the pediatric MS network, which is both a national and international network of centers of excellence with specialists that really focus on pediatric neuroimmunologic diseases, including MS. With the data that we're able to collect and accrue from those registries, we are able, more and more, to conduct studies that are able to figure out exactly which medications may work better within pediatrics versus adults. Even though only fingolimod is the one that's FDA approved, we do have good evidence that many of the other treatments that we typically use for adults, including natalizumab, rituximab, ocrelizumab, and dimethyl fumarate, all of those seem to also be quite effective and have similar, we think, safety profiles, although we are still collecting more and more data in order to provide better evidence of this, but we are working very hard to provide, again, further data in order to make this clear to both pediatric patients as well as families that are involved with these types of diseases.

Glen Stevens, DO, PhD: Certainly, in the neuro-oncologic field, if we look at the percentage of patients that go on a clinical trial, it's sadly low, even though a glioblastoma is a very aggressive tumor, but if we look at the pediatric neuro-oncology field, two-thirds of children go on a clinical trial. Does it work that way in MS, or no? Do the children go on clinical trials, or you just treat them with the adult drugs off trial?

Aaron Abrams, MD: We are trying to come up with more clinical trials, and there are ones that are both ongoing as well as ones that are planning on being started soon. We are able to enroll pediatric patients in clinical trials, looking specifically at these types of medications, but in addition to that, because it's more difficult to do that, as you mentioned, in the pediatric population, we also are relying on a lot of both retrospective and prospective data from these types of clinical centers of excellence across the country and the world in order to help also clarify some of these questions. I do think that, of course, clinical trials are very, very important, but I think that having the data from these types of registries is also important in terms of, again, clarifying some of these questions so that we can then make better informed decisions on which treatments may work for which populations of patients.

Glen Stevens, DO, PhD: You talked a little bit about the cognitive issues with MS and kids, but what have we learned about managing pediatric MS that's different that our listeners should know versus adult?

Aaron Abrams, MD: Pediatric MS, when it initially presents, it's typically more highly inflammatory with the clinical event. When we do imaging or we do CSF analysis of patients with a first onset of demyelination in the pediatric age group, we tend to see a higher degree of inflammation. That is both evidenced by higher cell counts and higher protein levels in the cerebral spinal fluid, but also on more extensive lesions, as well as enhancement patterns within MRI and neuroimaging techniques.

One of the very interesting things about pediatrics, and we think that this may have to do to some extent with plasticity and the ability of young pediatric brains to bounce back from neurological insults, is that they seem to recover much better and faster than a lot of the adult counterparts. Even though the initial event is oftentimes more highly inflammatory and potentially is more severe, pediatric patients oftentimes will actually recover much better.

The other important differences between pediatrics and adult MS is that in pediatric MS we find that typically in terms of the outcomes, a lot of times with things like MOG, which is, again, a myelin oligodendrocyte glycoprotein-associated disease, we find that pediatric patients are more likely to have what we call a monophasic course, which means that they're more likely to have one relatively significant clinical event, but then may not have any further clinical events. Whereas, adult counterparts are more likely to have multiple events.

Lastly, the big difference is also that with pediatric MS, it's much more common and almost always presents in a relapsing or remitting form, as opposed to adult MS, which oftentimes can present initially both with primary progressive, but also when it presents with relapsing-remitting, it can then transform into what we call secondary progressive. Pediatric MS is unique in the sense that almost always it presents in a relapsing-remitting form, and then it can much later on in life transition to these other entities, but it's much, much less likely.

Glen Stevens, DO, PhD: When I trained back many years ago, MS was thought to be a purely white matter disorder, and then there's more interest over the years of gray involved. Certainly with the cognitive issues that you suggest in the kids makes me think that gray matter would be involved more. What do we know about that in terms of the distribution?

Aaron Abrams, MD: Yeah, it's a very interesting point. I think that specifically, again using the example of MOG antibody disease or MOG-associated disease, we find more and more that MOG seems to involve the gray matter much more than a lot of these other types of demyelinating diseases like MS. I think that we do tend to see MOG more within the pediatric age group. I think that's increasing because of, again, our robustness in both detecting and confirming that specific antibody in the blood. I think that it could beg the question of whether in pediatrics, could there be a higher level in some of these demyelinating diseases for more gray matter involvement, and could that potentially implicate why we do see sometimes more prominent cognitive effects, although we do clearly see very prominent cognitive dysfunction and difficulties in adult MS as well and adult demyelinating diseases. But I think it's a very interesting question that warrants further research and exploration to see why we're seeing, to some extent, more gray matter involvement within some of these diseases.

Glen Stevens, DO, PhD: I know our listeners/readers are always interested in what's on the horizon. What's on the horizon? Where are we going? What's next? What's exciting?

Aaron Abrams, MD: I think within the pediatric neuroimmunological field, the main thing, which we've discussed, is really focusing on treatment. I think one of the big things that we're seeing is that early treatment with pediatric-onset demyelinating diseases, as well as robust treatment with some of these what we call higher efficacy treatments, which tend to have more side effects but also tend to be more effective with the way that they control the disease and prevent further neurological problems down the line, what we are finding based off of the evidence is that the earlier and the higher efficacy the medication we give when there is an initial onset of a pediatric demyelinating disease like MS, the much better the outcome in terms of future neurological functioning down the line. I think that that's a big thing, is really focusing on making sure and providing as much data as we can that these medications are safe and effective within pediatrics as we have shown they are in the adult population. I also just think that it's very important, given how rapidly the field is moving and changing and how much on a daily basis we're discovering about these complex disease entities, that anybody, any family member or child, who is concerned about some sort of a neuroimmunological disease, I would really encourage and stress that you seek out a specialist in order to really, fully evaluate and work it up in order to then be able to provide the most information and the best therapeutics that we have available to date.

Glen Stevens, DO, PhD: Any closing comments for our listeners?

Aaron Abrams, MD: I think that in line with what I've been saying about really making sure that you're evaluated by a specialist, I think that somewhere like Cleveland Clinic is a great place because of the collaborative care that Cleveland Clinic provides, as well as the multidisciplinary approach, I think is very important for these types of very complicated neuroimmunological diseases that can involve other organ systems as well as different aspects of the immune system and the neurological system. I think that it's a very good place to seek out care, and I think that it's somewhere that is a very good place for both management as well as treatment for a lot of these patients that we encounter in our practice.

Glen Stevens, DO, PhD: Well, Aaron, I'd like to thank you for joining me today. It's been enlightening and informative. I certainly know more about pediatric MS than I did before I started so I appreciate all your research and clinical efforts, thank you very much.

Aaron Abrams, MD: Thank you so much, it's been a pleasure to be here.

Closing: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, ClevelandClinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. Don't forget, you can access real time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website, that's ConsultQD.ClevelandClinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. Thank you for listening.